Methods: To further investigate the protection conferred by maternal CMV-neutralizing antibodies, 6 rhCMV-seronegative rhesus macaque dams in the second trimester of pregnancy were CD4+ depleted. One week later, 3 dams were administered a single dose (100mg/kg) of hyperimmune globulin (HIG) with a low neutralizing potency (IC50=22.64µg/mL) 1 hour prior to intravenous (IV) challenge with a mixture of fibroblast-adapted (180.92) and epithelial-tropic (UCD52/UCD59) rhCMV strains. The remaining 3 dams received 2 doses (125+100mg/kg) of a potently-neutralizing HIG product (IC50=5.88µg/mL) at 1 hour prior to IV rhCMV inoculation and 3 days post-infection, respectively.
Results: Passive infusion of HIG prior to IV rhCMV challenge of CD4+ depleted dams provided complete protection against fetal loss (0/6 dams aborted; p<0.01). Furthermore, 2 doses of the highly-neutralizing HIG product achieved protection from placental transmission of rhCMV (0/3 transmitted), while a single dose of low-potency HIG product did not (2/3 dams transmitted). Peak plasma viral load was decreased in all HIG treated animals. Furthermore, targeted deep sequencing of rhCMV glycoprotein L (gL) and glycoprotein B (gB) from maternal plasma revealed that infused HIG created a genetic bottleneck, decreasing the diversity of viral haplotypes at both loci.
Conclusion: Our data suggest that the presence of highly-neutralizing antibodies at the time of rhCMV acquisition can prevent congenital infection, perhaps by influencing early viral replication. A better understanding of how antibody-mediated selection impacts placental rhCMV transmission and fetal outcome will inform future vaccine development efforts.
D. Tran, None
A. Kaur, None
S. Permar, None
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